bhatt cogent
TRANSCRIPT
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The COGENT TrialThe COGENT Trial
Deepak L. Bhatt MD, MPH, Byron Cryer MD, Charles F. ContantPhD, Marc Cohen MD, Angel Lanas MD, DSc, Thomas J.
Schnitzer MD, PhD, Thomas L. Shook MD, Pablo Lapuerta MD,Mark A. Goldsmith, MD, PhD, Benjamin M. Scirica MD, Robert P.
Giugliano MD, Christopher P. Cannon MD,
on Behalf of the COGENT Investigators
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Disclosure for Dr. Bhatt
Dr. Bhatt has served as a consultant to: Arena, Astra Zeneca, Bristol-MyersSquibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline,Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips,Portola, sanofi aventis, Schering Plough, Takeda, The Medicines Company,Vertex.
Principal Investigator for several potentially related studies. His institution hasreceived funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, SanofiAventis, The Medicines Company.
This presentation discusses off-label and/or investigational uses of various drugsand devices.
The trial was funded by Cogentus, though no funding received for these analyses.
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GI bleedingDual antiplatelet therapy
Concomitant anticoagulant
Algorithm to Assess GI Risk WithAntiplatelet Therapy
Assess GI risk factors
History of ulcer complicationHistory of ulcer disease (nonbleeding)Test for H pylori ;treat if infected
More than one risk factor:Aged 60 years or moreCorticosteroid useDyspepsia or GERD symptoms
Need for antiplatelet therapy
Yes
Yes
NoPPI
Yes
Yes
Bhatt DL, Scheiman J, Abraham NS, et al. JACC 2008:52:150217. Circulation 2008. AJG 2008.
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Clopidogrel is a prodrug; requires conversion by theClopidogrel is a prodrug; requires conversion by theliver primarily via CYP3A4 and CYP2C19 to anliver primarily via CYP3A4 and CYP2C19 to anactive metaboliteactive metabolite
PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity
Clopidogrel and PPIs The OCLA studyClopidogrel and PPIs The OCLA study
-32.6
-43.3-50-45-40-35-30-25
-20-15-10
-50
P R I V a r i a t i o n ( % )
Omeprazole (n=64)
Placebo (n=60)
PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)
Gilard et al. J Am Coll Cardiol 2008;51:256-60.
p
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Risk of All-Cause Mortality and RecurrentACS in Patients Taking Clopidogrel and PPI
Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9):937-944.
0.70
0.60
0.50
0.40
0.30
0.20
0.10
00 90 180 270 360 450 540 630 720 810 900 990 1080
Days Since Discharge
P r o p o r t
i o n o
f
D e a
t h s o r
R e c u r r e n
t A C S
Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI
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C V d e a
t h ,
M I o r s
t r o
k e
Days
CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11
PPI use at randomization (n= 4529)
Clopidogrel
Prasugrel
PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20
Primary endpoint stratified by use of a PPI
ODonoghue ML, Braunwald E, Antman EM, et al. Lancet . 2009.
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Aims
To determine whether PPI versus placebo reduced important GI
events in patients on dual antiplatelet therapy
To determine if there was any cardiovascular interaction between
clopidogrel and PPI
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Methods
Multicenter, international, randomized, double-blind,double-dummy, placebo-controlled, parallel group, phase3 efficacy and safety study of CGT-2168, a fixed-dosecombination of clopidogrel (75 mg) and omeprazole (20mg), compared with clopidogrel.
Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant useof any NSAID.
All patients were to receive enteric coated aspirin at a
dose of 75 to 325 mg.
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Methods
The GI endpoint was upper GI bleeding, bleeding of presumed occult GI
origin with decrease in hemoglobin of 2 g/dL or decrease inhematocrit 10%, symptomatic gastroduodenal ulcer confirmed byendoscopy or radiography, pain of presumed GI origin with underlyingmultiple erosive disease confirmed by endoscopy, obstruction, or perforation.
The cardiovascular endpoint was the composite of cardiovascular death, non-fatal MI, CABG or PCI, or ischemic stroke.
Adjudication of events was performed by an independent committee of cardiologists and gastroenterologists.
The initial planned sample size was 3200 patients, an accrual period of 1 year, and maximum follow up of 2 years. As a low rate of gastrointestinal events was observed as the trial was ongoing, thesample size target was increased to 4200 and then ~5000 (143 GI
events). The study ended when the sponsor declared bankruptcy.
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Inclusion Criteria
Patients 21 years of age
Clopidogrel therapy with concomitant aspirin was anticipated for at least
the next 12 months
acute coronary syndrome
undergoing placement of a coronary stent
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Exclusion Criteria
Hospitalized patients for whom discharge was not anticipated within 48 hours of randomization
Requirement for current or chronic use of a proton pump inhibitor, H2 receptor blocker, sucralfate or
misoprostol
Erosive esophagitis, esophageal, or gastric variceal disease, or non-endoscopic gastric surgery
Receipt of > 21 days of clopidogrel or another thienopyridine prior to randomization
Oral anticoagulation that cannot be safely discontinued for duration of study
Recent fibrinolytic therapy
Scheduled PCI or recent (< 30 days prior to randomization) CABG
Active bleeding or a history of a hemostatic disorder
Systemic corticosteroids except low-dose oral corticosteroids equivalent to prednisone 5 mg/day
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Results
3627 patients (above the initial target of 3200)
393 sites
Median follow-up 133 days (maximum 362 days)
136 adjudicated cardiovascular events ( preliminary )
105 adjudicated GI events ( preliminary )
143 had been planned
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Baseline Characteristics
0.0611313 (69.6)1251 (66.7)Sex Male
0.65529.2 kg/m 2 (5.3)
28.3
29.2 kg/m 2 (5.6)
28.4
BMI
0.98467.2 years (11.1)68.6 years
67.2 years (10.8)68.7 years
Age
Mean (SD)Median
Mean (SD)Median
0.757114 (6.1)208 (5.8)History of Stroke
0.426158 (8.5)172 (9.3)History of PAD
0.468466 (25.0)484 (26.1)History of MI
0.382699 (37.5)669 (36.1)History of ACS0.8081769/63/561756/68/51White/Black/Other
0.456105 (5.6)116 (6.2)Used NSAIDs
0.938926 (49.0)923 (49.2)H. Pylori Positive
p-value for differencePlacebon (%)Treatedn (%)Variable
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Days
S u r v
i v a
l P r o
b a
b i l i t y
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0 . 9
0
0 . 9
2
0 . 9
4
0 . 9
6
0 . 9
8
1 . 0
0
Placebo
Treated
Survival Curves for PPI Treated vs PlaceboComposite Cardiovascular Events
Adjustment through Cox Proportional Hazards Model Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 1.0295% CI = 0.70; 1.51
Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk
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Days
S u r v
i v a
l P r o
b a
b i l i t y
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0 . 9
0
0 . 9
2
0 . 9
4
0 . 9
6
0 . 9
8
1 . 0
0
PlaceboTreated
Survival Curves for PPI Treated vs PlaceboMI Events
Adjustment through Cox Proportional Hazards Model Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 0.9695% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk
Treated: 36 events, 1839 at risk
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Days
S u r v
i v a
l P r o
b a
b i l i t y
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0 . 9
0
0 . 9
2
0 . 9
4
0 . 9
6
0 . 9
8
1 . 0
0
Placebo
Treated
Survival Curves for PPI Treated vs PlaceboRevascularization
Adjustment through Cox Proportional Hazards Model Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 0.9595% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
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Hazard Ratio
0 2 4 6 8 10
H. pylori Positive or Indeterminate
H. pylori Negative
No NSAIDs Used
NSAIDs Used
Male
Female
Other Race
Black
White
Age 70
BMI 30
Overall
Composite Cardiovascular Event HazardRatios for Baseline Variables
Vertical Line is Overall Hazard
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Composite Cardiovascular Event HazardRatios for Medical History Variables
Hazard Ratio
0 1 2 3 4
History of ACS Negative
History of ACS Positive
History of MI Negative
History of MI Positive
History of PAD Negative
History of PAD Positive
History of Stroke Negative
History of Stroke Positive
History of Other Negative
History of Other Positive
Overall
Vertical Line is Overall Hazard
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Days
S u r v
i v a
l P r o
b a
b i l i t y
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0 . 9
0
0 . 9
2
0 . 9
4
0 . 9
6
0 . 9
8
1 . 0
0
Placebo
Treated
Survival Curves for PPI Treated vs PlaceboComposite GI Events
HR = 0.5595% CI = 0.36; 0.85
p=0.007
( preliminary )
Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk
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Limitations
Due to premature termination of trial, limited follow-up
However, most relevant for GI events, as most cardiac events early after ACS or
PCI
No current PPI/clopidogrel data set has more adjudicated CV endpoints
May not be directly applicable to PPIs other than omeprazole
Most commonly used PPI
One most indicted by ex vivo studies
Special formulation of clopidogrel/PPI with different release kinetics, so may not be
the same as taking clopidogrel and omeprazole off the shelf
If a major concern, then take the clopidogrel in the morning and the PPI at night
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Conclusions
COGENT is the first, randomized assessment of clopidogrel and PPIs on clinical
events
The data provide strong reassurance that there is no clinically relevant adverse
cardiovascular interaction between clopidogrel and PPIs
The results call into question the exact relationship between ex vivo platelet assays
and clinical outcomes, especially with respect to assessing drug interactions
Platelet assays and observational data are not a substitute for RCT data
Further research is needed to define the optimal strategy to reduce GI events in
patients on antithrombotic therapy, though prophylactic PPIs seem very promising